Pharmacology Of Drugs For Anemia 423115

PHARMACOLOGY OF DRUGS FOR ANEMIA

Dr.Datten Bangun MSc.SpFK Dept.Farmakologi & Therapetik Fak.Kedokteran UHN

ANEMIA Anemia can be defined as a reduction in the hemoglobin,hematocrit or red cell number. In physiologic an anemia is any disorder in which the patient suffers from tissue hypoxia due to decreased oxygen carrying capacity of the blood

Hematinics These are drugs used to treat anemia Iron Vitamin B12, Cyanocobalamin Folic acid Erythropoietin

TYPES OF ANEMIA ►Various classifications: ►Examples: ►Iron deficiency anemia ---microcytic , hypochromic ►Megaloblastic anemia ---macrocytic , normochromic due to Vit. B12 or Folic Acid deficiency ►Anemia due to decreased Erythropoietin 4

Causes of Anemia • 1. Diminished production and or replacement of red blood cells. • 2. Excessive breakdown and loss of red blood cells. • Hemodilution while not a cause of anemia, it does cause an anemialike effect.

1. Diminished Production/Replacement of RBC’s Anemia's

• Microcytic anemia – deficiency of Fe

• RBC’s appear pale and smaller, and we see more reticulocytes in circulation. • Can be caused by the chronic use of aspirin, which irritates the stomach GI blood loss.

• Normocytic anemia – deficiency of Erythropoietin • Caused by compromised renal function.

• Macrocytic Anemia- deficiency of folic acid and B12 • Diminished cell division and release of larger cells in circulation.

2. Breakdown of RBC’s Anemia • Bleeding: can be due to an ulcer or in females blood loss due to their menstrual cycle • Use of drugs that irritate the GI tract (aspirin) • Hemolysis (Hemolytic Anemia) can be caused by: • Autoimmune disease • Mechanical (heart valves, microvascular disease) • Toxins (e.g., snake venom)

Anti anaemic Drugs • Haematopoiesis: it is the production of erythrocytes, platelets, and leukocytes from undifferentiated stem cells. • The haematopoietic machinary reside in the bone marrow in adults. • It requires a constant supply of essential nutrients – iron, vit B12, folic acid and presence of hematopoietic growth factors

ANTI-ANEMIC DRUGS ►Drugs effective in iron deficiency and other hypochromic anemias: ►Iron ►Pyridoxine , Riboflavin , Copper ►Drugs effective in megaloblastic anemia: ►Vitamin B12 ►Folic Acid 9

IRON FACTS All body cells need iron. It is crucial for oxygen transport, energy production, and cellular growth and proliferation. The human body contains an average of 3.5 g of iron (males 4 g, females 3 g). The typical daily normal diet contains 10–20 mg of iron. Only about 10% of dietary iron is absorbed (1–2 mg/day).

Anti anaemic Drugs • Iron: Total quantity of iron in the body is 4-5G, 65-70% in the form of Hb in RBC, 4% in myoglobin, 1% in various heme compound, 15-30% stored in the form of ferritin and hemosiderin in RE system, liver, spleen, intestinal mucosa and bone marrow •

IRON Preparations:  Oral: Ferrous sulphate Ferrous gluconate Ferrous fumarate , etc.  Parenteral: Iron dextran ---- i.m or i.v Iron Sorbitol ----- i.m only. 12

Pharmacokinetics   Absorption ---- depends on ► requirements ► iron stores ► Ferrous (Fe++) / ferric (Fe+++) form ► pH ► Vitamin C ► Chelators or complexing agents

13

Iron transport • Most absorbed iron is transported in the bloodstream bound to the glycoprotein transferrin. • Transferrin is a carrier protein that plays a role in regulating the transport of iron from the site of absorption to virtually all tissues. • Transferrin binds only two iron atoms. • Normally, 20–45% of transferrin binding sites are filled (measured as percent transferrin saturation [TS]).

Iron transport

Ferritin molecules store thousands of iron atoms within their mineral core. When excess dietary iron is absorbed, the body responds by producing more ferritin to facilitate iron storage.

Importance of Iron Iron forms the nucleus of the iron-porphyrin heme ring, This with globin chains forms hemoglobin. Function of Haemoglobin: Reversibly binds oxygen and provides the critical Mechanism for oxygen delivery from the lungs to other tissues. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to Microcytic hypochromic anemia

Acute Oral toxicity (overdose ; poisoning) ► Necrotizing gastroenteritis with ---vomiting, abdominal pain, bloody diarrhea ► Shock , lethargy & dyspnea ► Severe metabolic acidosis ► Coma ► Death

18

Acute Oral toxicity (overdose ; poisoning): (Contd.)

Treatment: ► Whole bowel irrigation ► Desferrioxamine (Deferoxamine) ► orally --- for Unabsorbed iron ► Parenteral ( i.m. , i.v. ) --- for iron absorbed Desferrioxamine + ferric iron

Ferrioxamine --- excreted in

19

Chronic iron toxicity (iron overload): (Contd.) Hemosiderosis: a focal or general increase in tissue iron stores without associated tissue damage Hemochromatosis: associated with tissue damage

20

Chronic iron toxicity (iron overload) (Contd.) Treatment: ► Intermittent Venesection (Phlebotomy)---when there is no anemia ► Chelation (Desferrioxamine) ---for transfusional overload 21

Adverse effects of Parenteral iron therapy ► Local pain & tissue staining – (brown discoloration of tissue overlying the injection site). ► Headache , light-headedness , fever , arthralgias, ► nausea , vomiting , back pain , flushing , urticaria, bronchospasm , & ,

22

VITAMIN B12 Chemistry ► Porphyrin-like ring with a central cobalt atom & nucleotide. ► Cobalamins = various organic groups covalently bound to cobalt atom Cyanocobalamine hydroxycobalamin & other cobalamins (found in food sources) are converted 23

► Active forms of vitamin B12 in human: Deoxyadenosylcobalamin Methylcobalamin ► Vitamin B12 available for therapeutic uses: Cyanocobalamin Hydroxycobalamin Hydroxycobalamin --- is preferred because

24

Pharmacokinetics ► Absorption: ► Intrinsic factor (IF) --- a glycoprotein , secreted by parietal cells of gastric mucosa ► IF-Vit.B12 Complex --- absorbed by active transport in the distal ileum ► Transported in plasma bound to the 25

Pharmacokinetics (Contd.) Route of istration ► Mostly ------ Parenteral ---- i.m. ► Oral ► Aerosol

26

Pharmacokinetics (Contd.) Elimination: ► not significantly metabolized ► into bile ► Enterohepatic circulation ► Excreted via kidney 27

Features of Vitamin B12 deficiency Impairment of DNA synthesis affects all cells but most apparently RBCs. ► Megaloblastic Anemia ► GI symptoms ► neurologic abnormalities 28

Features Vitamin B12 deficiency (Contd.) Neurological abnormalities : Degeneration of brain and spinal cord (Subacute combined degeneration ) and peripheral nerves. Symptoms may be psychiatric & physical. Paresthesia & weakness in peripheral nerves spasticity, ataxia, & other CNS

29

Uses ► ► ► ►

Pernicious (addisonian) anemia After partial or total gastrectomy Malabsorption syndromes Insufficient dietary intake

► Hydroxycobalamin (Not cyanocobalamin) ► Tobacco Amblyopia ► Cyanide toxicity 30

Adverse effects ►Allergic hypersensitivity reactions ►Antibodies to hydroxycobalamintranscobalamin II complex ►Arrhythmias secondary to hypokalemia

31

FOLIC ACID (PTEROYLGLUTAMIC ACID; VITAMIN B9) ► Is inactive ► Active form is ---- tetrahydrofolic acid

32

Pharmacokinetics ► Route of istration ----- usually oral ► In diet ---- Polyglutamate form ► For absorption ---- must be converted to --Mono-glutamyl form ► Absorbed mostly --- in proximal jejunum 33

Functions ► Is required for synthesis of Amino acids , purines, pyrimidines, & DNA ; & therefore in the cell division

34

Features of folic acid deficiency ► Mitotically active tissues such as erythroid tissues are markedly affected.

► Anemia ► Congenital malformations --neural tube defects ( e.g., spina bifida) ► Vascular disease

35

Vitamin C Vitamin C deficiency can cause megaloblastic anemia

36

Uses Prevention & treatment of folic acid deficiency ► Dietary insufficiency (e.g. in elderly) ► Pregnancy & lactation ► to prevent --- Congenital malformations --neural tube defects ( e.g., spina bifida) ► High red cell turn over --- e.g. in 37

Uses (contd.) ► Drugs ► Antiepileptics ---- enzyme inducers ► Phenytoin ► Primidone ► Phenobarbitone ► Antimalarials ► pyrimethamine ► Methotrexate 38

Uses (contd.) ► ► ► ► ►

Myelofibrosis Exfoliative dermatitis Rheumatoid arthritis Malignant disease , e.g., lymphoma Chronic hemodialysis

39

Adverse effects ► Generally well tolerated ► Rarely --► G.I. Disturbances ► hypersensitivity reactions ► Status epilepticus may be precipitated

40

ERYTHROPOIETIN (EPOTEIN) ► a glycoprotein hormone ► produced : 90% --- by peritubular cells in kidney remainder --- by liver and other tissues ► is essential for normal reticulocyte production ► synthesis is stimulated by hypoxia   ► synthesized for clinical use ---- by 41

Pharmacokinetics ►Route of istration --- S.C. or I.V. ►Plasma t1/2 ---- 4 - 13 hrs in patients with chronic renal failure.   ►Not cleared by dialysis 42

Mechanism of action ►increases rate of stem cell differentiation ►increases rate of mitosis in red cell precursors, blast-forming units, colony forming cells. ►increases release of reticulocyte from marrow ►increases Hb synthesis ►its action requires adequate stores of iron 43

Uses ►Anemia associated with chronic renal failure ►premature infants ►Anemia during chemotherapy of cancer ►Anemia of AIDS (which is exacerbated by zidovudine treatment) ►to increase the yield of autologous blood before donation 44

Adverse effects ► Usually due to excessive increase in hematocrit ►increase blood pressure ►thrombosis ►seizures ►headache ►hypertensive crises with encephalopathy-like symptoms 45

Adverse effects ►Transient influenza-like symptoms -----chills & myalgias ► iron deficiency ►transient increases in platelet count ►hyperkalemia ►skin rashes ►pure red cell aplasia --- discontinue the drug 46

Precautions / contraindications ►hypertension should be well controlled ► seizures ►thrombocytosis ►ischemic vascular disease ►iron , folic acid , vit. B12 supplements may be needed ►heparin during dialysis

47

Monitor ►hematocrit ►blood pressure ►platelet count ►serum potassium

48